tbuckley/cabot-search huggingface dataset:
Abstract 4988: A tailored platform enables BRAF-targeted drug discovery and precision medicine
Authors: Hui Qi, Fuyang Wang, Bingrui Han, Xiaomin Wang, Xiangnan Qiang, Zhixiang Zhang, Qingyang Gu
Journal: Cancer Research (2023)

Abstract Mutant BRAF, one of the most frequently mutated serine/threonine kinase, drives tumorigenesis via activating MAPK signaling across various tumor types. Expanded genomic and mechanistic studies over the past two decades have revealed the heterogeneity regarding BRAF mutation status and characterized a classification system for BRAF mutations based on their mode of action. Class I (V600 mutants) and class II (K601 mutants, G469A/V/R, etc) BRAF mutants function as RAS-independent active monomers or dimers to amplify MAPK signaling, whereas class III (G466 mutants, D594 mutants, G469E, etc) mutants, which are kinase impaired or dead, promote MAPK signaling via enhanced RAS binding and subsequent CRAF activation. To date, combination therapies of BRAF and MEK inhibitors have been approved for treatment of patients harboring class I BRAF mutations, while viable therapeutic options for those with class II and III BRAF mutations are still ambiguous. Therefore, developing new drugs and personalized therapeutic strategies directing different classes of BRAF mutations, especially class II and III subtypes, have become vital in the war against BRAF-mutant tumors. To enable BRAF-targeted drug discovery and precision medicine, we developed a tailored platform based on the classification of BRAF mutations, which integrates whole exome sequencing (WES) for identification of mutant BRAF subtypes with in vivo efficacy evaluation in patient-derived tumor xenograft (PDX) models. Our platform covers all three classes of BRAF mutants, such as V600E/G469A/D594N/G469E. Moreover, this platform faithfully recapitulate the responses of multiple targeted therapies, such as BRAF, MEK and EGFR inhibitors, reported for treating BRAF-mutant tumors in preclinical and clinical studies, highlighting the potential translation values. Taken together, the platform reported in this study empowers the discovery of novel BRAF inhibitors that can be translated into clinical trials and provides personalized therapeutic options for patients who have poorly responded to standard clinical therapies. Citation Format: Hui Qi, Fuyang Wang, Bingrui Han, Xiaomin Wang, Xiangnan Qiang, Zhixiang Zhang, Qingyang Gu. A tailored platform enables BRAF-targeted drug discovery and precision medicine. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4988.
Abstract 2993: Unmutated tumor antigens are abundant and contribute to tumor control in melanoma
Authors: Anca Apavaloaei, Qingchuan Zhao, Leslie Hesnard, Krystel Vincent, Marie-Pierre Hardy, Chantal Durette, Joël Lanoix, Jean-Philippe Laverdure, Jean-David Larouche, Maria Virginia Ruiz Cuevas, Grégory Ehx, Sébastien Lemieux, Pierre Thibault, Claude Perreault
Journal: Cancer Research (2023)

Abstract Recognition of MHC-I-associated tumor antigens (TAs) by CD8+ T cells is central to antitumor immunity. Owing to the elevated tumor mutational burden (TMB) in melanoma, the marked efficacy of immune checkpoint blockade (ICB) has been attributed to the recognition of mutated TAs. However, recent reports showed that response to ICB in melanomas with low TMB is associated with CD8+ T-cell reactivity against melanocyte lineage-associated antigens (LSAs). Here, we systematically evaluated the contribution of all TA classes, i.e., mutated and unmutated, canonical and non-canonical, to the antigenic landscape of melanoma. We characterized the TAs from melanoma biopsies and patient-derived cell lines using proteogenomics. Out of 79450 MHC-I-associated peptides (MAPs) identified from 19 samples, we found 557 unmutated TAs classified as tumor-specific (TSA), tumor-associated (TAA), or LSAs. These TAs most often derived from annotated open-reading frames, followed by ncRNAs and intergenic regions. By contrast, only 6 MAPs were mutated and tumor-specific, which could be partially explained by a decreased expression of mutations within MAP-generating genomic regions. While the number of unmutated TAs with predicted presentation (TApres) in melanoma patients was similar between responders and non-responders pre-ICB, non-responders showed marks of inefficient antigen presentation. In consequence, only responders lost TApres upon treatment, in tandem with an expansion in tumor-infiltrating lymphocytes. These results reveal a previously underappreciated contribution of unmutated TAs to tumor control in melanoma and suggest that enhancing their recognition could improve the ICB efficacy in non-responders. Citation Format: Anca Apavaloaei, Qingchuan Zhao, Leslie Hesnard, Krystel Vincent, Marie-Pierre Hardy, Chantal Durette, Joël Lanoix, Jean-Philippe Laverdure, Jean-David Larouche, Maria Virginia Ruiz Cuevas, Grégory Ehx, Sébastien Lemieux, Pierre Thibault, Claude Perreault. Unmutated tumor antigens are abundant and contribute to tumor control in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2993.
Abstract 2830: Fluoxetine mediate radiosensitivity and inhibit metastasis of osteosarcoma cells via RANK/RANKL signaling
Authors: Peggy Tan, Jai-Jen Tsai, Fei-Ting Hsu, Yu-Chiang Liu
Journal: Cancer Research (2023)

Abstract Osteosarcoma (OS) is most common primary malignant bone tumour OS was flagrantly byaffecting pediatric and young adolescents patients with its outrageous metastatic rate and poorprognosis. It was aggressive in local invasion and further metastasis, especially pulmonarymetastasis. Radiotherapy (RT) was a clinical treatment method that using high-energy ionizingradiation to control tumour growth with low risk and considerably successful rate.Contradictorily, OS was recognized as radio-resistant tumour. Meanwhile, majority of OScases were diagnosed suffering depression and influence patient’s conditions critically. Hence,aim of this prospective study was to identify that combinational therapeutic efficacy ofradiation therapy and fluoxetine (Prozac) through mediating radiosensitivity and inhibitmetastasis of OS cells via RANK/RANKL signaling. OS cell lines U2OS and MG63 were usedin this study. To investigate the cells survival fraction, clonogenic assay were performed. Next,to examine metastasis and invasions of cells wound healing assay and transwell assay werecarried out. Furthermore, TUNEL assay was used to evaluate DNA damage of OS cells.Fluoxetine effectively inhibited the metastasis and invasion ability of OS cells. Thecombinational therapy of fluoxetine and RT successfully decreased the surviving fraction ofOS cells and induced the damage of DNA. Additionally, the protein expression ofRANK/RANKL was markedly suppressed by fluoxetine as illustrated by Western blottingassay. In sum, the combination treatment of radiotherapy with the interrelation of fluoxetinewas showing its potential and consider as new treatment strategy might elevate treatmentefficacy for OS. Keywords: Osteosarcoma (OS), Radiotherapy (RT), Fluoxetine, RANK/RANKL Citation Format: Peggy Tan, Jai-Jen Tsai, Fei-Ting Hsu, Yu-Chiang Liu. Fluoxetine mediate radiosensitivity and inhibit metastasis of osteosarcoma cells via RANK/RANKL signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2830.
Abstract 5331: DNA-encoded macrocyclic compound libraries for challenging targets
Authors: Ying Zhang, Anthony Keefe, Paolo Centrella, John Cuozzo, Holly Soutter, Daniel Resnicow, Sevan Habeshian, Matt Clark
Journal: Cancer Research (2023)

Abstract Increasingly drug discovery programs require the development of orally available and cell permeable classes of drugs derived from the chemical space beyond Lipinski’s rule of 5 (bRO5). The chameleon-like physicochemical properties and differentiated binding modes of bRO5 compounds make them suitable starting points, especially for difficult-to-drug targets beyond traditional small molecule drug discovery. The synthesis of macrocyclic (MC) peptide DNA-Encoded Libraries (DEL) aligns with these efforts and has been an important addition to the rapidly growing field of DNA-encoded small molecule library screening. DEL screening of de novo designed bRO5 compounds will aid the exploration of bRO5 chemical space. X-Chem’s macrocyclic compound libraries apply chemistries beyond traditional peptide formation and extend to the inclusion of diverse building block classes. A case study of a successful screening campaign utilizing these MC DEL for Bcl2 will be presented. Citation Format: Ying Zhang, Anthony Keefe, Paolo Centrella, John Cuozzo, Holly Soutter, Daniel Resnicow, Sevan Habeshian, Matt Clark. DNA-encoded macrocyclic compound libraries for challenging targets. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5331.
Abstract 1645: JAB-2485: A potent, highly selective small-molecule Aurora kinase A inhibitor that targets cell division
Authors: Guiqun Yang, Yanping Wang, Haijun Li, Mingming Chen, Yiwei Lin, Xin Sun
Journal: Cancer Research (2023)

Abstract Background: Aurora kinase A (AURKA), a crucial mitotic regulator, is frequently dysregulated in a wide range of cancers and contributes to clinical aggressiveness and poor patient survival. Abnormally activated AURKA promotes tumorigenesis through enhancing cancer cell proliferation, epithelial-mesenchymal transition, and cancer stem cell self-renewal, rendering it an attractive therapeutic target. We have developed JAB-2485, a highly selective small-molecule AURKA inhibitor. Methods: Biochemical and cell-based assays were performed to determine the IC50 of JAB-2485 on Aurora kinase family members. Fluorescence activated cell sorting (FACS) and caspase 3/7 assay were performed to detect JAB-2485-induced cell cycle arrest and apoptosis, respectively. The CellTiter-Glo assay was performed to evaluate the effect of JAB-2485 in multiple cancer cell lines. Finally, the antitumor effect of JAB-2485 either as a single agent or in combinations was investigated in tumor cell line-derived xenografts. Results: JAB-2485 is potent and highly selective on AURKA, with IC50 of 0.33nM and around 1700-fold selectivity over AURKB. Following treatment of JAB-2485, the level of AURKA phosphorylation as a pharmacodynamic marker was significantly decreased in a dose-dependent manner. As a single agent, JAB-2485 inhibited in vitro proliferation of small cell lung cancer (SCLC), triple-negative breast cancer (TNBC) and neuroblastoma cell lines along with induced G2/M cell cycle arrest and apoptosis, and significantly inhibited in vivo tumor growth on SCLC and neuroblastoma xenografts. Furthermore, JAB-2485 showed strong synergy with cisplatin and paclitaxel in SCLC and TNBC animal models, respectively. Conclusions: Taken together, preclinical results provide robust evidence supporting further evaluation of JAB-2485 both as a single agent and in combinations for treatment of various types of cancers. A Phase 1/2a clinical trial of evaluating JAB-2485 in adult patients with advanced solid tumors is enrolling patients in the US (NCT05490472). Citation Format: Guiqun Yang, Yanping Wang, Haijun Li, Mingming Chen, Yiwei Lin, Xin Sun. JAB-2485: A potent, highly selective small-molecule Aurora kinase A inhibitor that targets cell division [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1645.
Abstract 299: Large tandem duplications in cancer resulting from transcription and DNA replication collisions
Authors: Yang Yang, Michelle Badura, Patrick O’Leary, Emily Egusa, Troy Robinson, Xiaoming Zhong, Jason Swinderman, Minkyu Kim, Haolong Li, Alan Ashworth, Felix Feng, Jonathan Chou, Lixing Yang
Journal: Cancer Research (2023)

Abstract Somatic structural variations (SVs) are common in cancer. Although a small fraction of SVs in breast and ovarian cancers can be attributed to homologous recombination deficiency, the underlying molecular mechanisms for the vast majority of somatic SVs remain unclear. Here, we focus on the roles of transcription and DNA replication collisions in genomic instability in cancer. Such collisions are unavoidable in cells since both transcription and replication use the same DNA as template. We hypothesized that transcription replication collisions (TRCs), if not properly repaired, would lead to collapsed replication forks and result in SVs. To this end, we studied somatic SVs in 5994 high-coverage whole-genome sequenced primary and metastatic tumors from three independent pan-cancer cohorts. A total of 12 conserved SV signatures, representing independent molecular mechanisms, were deconvoluted from these cohorts using non-negative matrix factorization approach. We detected replicated-strand bias, the expected footprint of transcription-replication collision, in large tandem duplications (TDs) across multiple cohorts. This bias was only observed in expressed genes, consistent with TRCs depending on transcription activity. Large TDs were abundant in female-specific (breast, ovarian and uterus), upper gastric-intestinal tract and prostate cancers. They were associated with worse patient survival and TP53 and CDK12 mutations. CDK12 is a cyclin-dependent kinase (CDK) and a key regulator of transcription elongation. Deleting or suppressing CDK12 using CRISPR-Cas9 in prostate cancer cell lines not only increased RNA:DNA hybrids (R-loops), but also promoted TRCs, suggesting a mechanism by which dysregulation of a transcriptional CDK may lead to genomic instability. Finally, using existing large-scale drug screening data, we found that cancer cell lines with abundant large TDs were significantly more sensitive to the WEE1 inhibitor, MK-1775, which we experimentally validated in prostate cancer cells lacking CDK12. In summary, our data suggest that large TDs in cancer form due to impaired TRC repair and can be used as a biomarker for prognosis and treatment. Citation Format: Yang Yang, Michelle Badura, Patrick O’Leary, Emily Egusa, Troy Robinson, Xiaoming Zhong, Jason Swinderman, Minkyu Kim, Haolong Li, Alan Ashworth, Felix Feng, Jonathan Chou, Lixing Yang. Large tandem duplications in cancer resulting from transcription and DNA replication collisions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 299.
Abstract 6525: Colon cancer screening and treatment with engineered probiotics
Authors: Candice R. Gurbatri, Georgette Radford, Jongwon Im, Courtney Coker, Nicholas Arpaia, Susan L. Woods, Daniel L. Worthley, Tal Danino
Journal: Cancer Research (2023)

Abstract Bioengineered probiotics enable new opportunities to improve colorectal cancer (CRC) screening, prevention and treatment strategies. Here, we demonstrate selective colonization of CRC tumors with the orally-delivered probiotic E. coli Nissle 1917 (EcN) in genetically-engineered and orthotopic murine models of CRC, and human CRC patients. We subsequently engineer EcN to produce screening and therapeutic molecules, resulting in non-invasive detection of precursor CRC lesions and reduction of tumor burden through local induction of robust anti-tumor immunity. Citation Format: Candice R. Gurbatri, Georgette Radford, Jongwon Im, Courtney Coker, Nicholas Arpaia, Susan L. Woods, Daniel L. Worthley, Tal Danino. Colon cancer screening and treatment with engineered probiotics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6525.
Abstract 65: HIRA is a master regulator of the proliferation-to-dormancy switch in breast cancer
Authors: Stanislav Drapela, Devesh Raizada, Ananya Mukherjee, Joanne Tejero, Didem Ilter, Jose Javier Bravo-Cordero, Ana P Gomes
Journal: Cancer Research (2023)

Abstract Most cancer-related deaths are caused by recurrent metastatic disease with latency periods that range from years to even decades. This halt in disease progression is driven by cancer dormancy, a stage in which residual disease is present but remains asymptomatic before reawakening and often causes lethal forms of the disease. Cell fate decisions, such as the ones that underlie dormancy and reawakening of cancer cells, often require extensive epigenetic remodeling, which in turn allows for the expression of specific genetic programs that trigger cell fate decisions. Therefore, epigenetic remodeling is likely essential for the switch between dormant and proliferative states throughout the metastatic process. Here we focus on epigenetic regulator, histone H3.3 chaperone HIRA and its role in the proliferation-to-dormancy switch in breast cancer cells. In this study, we demonstrate that HIRA suppression leads to cell cycle arrest and induces canonical dormancy pathways via phosphorylation of p38 and induction of p27 expression. In addition, HIRA suppression triggers induction of stress-inducible transcription factors NRF2, MITF and ATF3 to enable the activation of genetic programs that maintain homeostasis and promote survival in dormant cells. Our data also portray that HIRA is suppressed in the well-established isogenic models of dormancy when compared to their metastatic counterparts. Altogether we present for the first-time histone chaperone HIRA as a major regulatory point of cell fate for disseminated cancer cells by controlling their transition between dormant and proliferative states, and therefore suggest HIRA as a novel and tremendously needed therapeutic target for metastatic breast cancer. Citation Format: Stanislav Drapela, Devesh Raizada, Ananya Mukherjee, Joanne Tejero, Didem Ilter, Jose Javier Bravo-Cordero, Ana P Gomes. HIRA is a master regulator of the proliferation-to-dormancy switch in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 65.
Abstract 2796: Tumor pharmacokinetics, pharmacodynamics and efficacy analysis of WEE1 inhibitor, zn-c3 in patient-derived xenograft models of glioblastoma
Authors: Shwetal Mehta, An-Chi Tien, Sonam Patel, Tigran Margaryan, Anilkumar Thaghalli Shivanna, Leonel Elena, Jennifer Molloy, William Knight, Ruiheng Hon, Mackenna Elliott, Mariya Stavnichuk, Zorana Opachich, Yu-Wei Chang, Chelsea Montgomery, Sarah Himes, Barbara Hopkins, Artak Tovmasyan, Nader Sanai
Journal: Cancer Research (2023)

Abstract WEE1 kinase regulates G2/M checkpoint transition via phosphorylation of CDK1 and prevents entry into mitosis. WEE1 inhibition increases genomic instability due to G2/M checkpoint inactivation and can result in mitotic catastrophe as monotherapy or when combined with DNA damaging agents. In this study, we evaluated the efficacy as well as pharmacokinetic and pharmacodynamic properties of ZN-c3, a best-in-class WEE1 inhibitor, in orthotopic patient-derived xenograft (PDX) models of GBM. Mice with intracranial tumors were randomized to 80 mg/kg ZN-c3 PO QD x 2 weeks vs. placebo. ZN-c3 levels in plasma and contrast-enhancing tumor tissue were measured by liquid chromatography tandem mass spectrometry (LC-MS/MS). Unbound fractions were determined by equilibrium dialysis. Immunohistochemistry was performed to assess levels of pCDK1, phospho-Histone H3 (pHH3), and cleaved caspase 3 (CC3). The median unbound concentrations of ZN-c3 were 315 nmol/L and 15 nmol/kg in plasma and tumor tissue, respectively - higher than the biochemical IC50 of ZN-c3 for inhibition of WEE1 (3.8nM). An increase in pHH3(+) cells (0.40% vs. 6.57%, p=0.03) indicated drug-induced mitotic entry upon ZN-c3 treatment. ZN-c3 was potently cytotoxic across multiple patient-derived xenograft (PDX)-derived cell lines (IC50- 150-10000nM). Time and dose-escalation experiments exhibited target engagement at concentrations lower than IC50 values within one hour of treatment. Basal levels of WEE1 and pCDK1 were correlated with cell viability in response to ZN-c3 across multiple PDX cell lines. Overall, ZN-c3 is well tolerated, achieves pharmacologically-relevant unbound concentrations in GBM PDX models, and is associated with significant checkpoint modulation. Preclinical evaluation of ZN-c3 in combination with radiation therapy and DNA damage response pathway inhibitors is currently underway, which will support future combinatorial strategy for glioblastoma treatment. Citation Format: Shwetal Mehta, An-Chi Tien, Sonam Patel, Tigran Margaryan, Anilkumar Thaghalli Shivanna, Leonel Elena, Jennifer Molloy, William Knight, Ruiheng Hon, Mackenna Elliott, Mariya Stavnichuk, Zorana Opachich, Yu-Wei Chang, Chelsea Montgomery, Sarah Himes, Barbara Hopkins, Artak Tovmasyan, Nader Sanai. Tumor pharmacokinetics, pharmacodynamics and efficacy analysis of WEE1 inhibitor, zn-c3 in patient-derived xenograft models of glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2796.